"Ghost Sweeper Mikami" centers on Reiko Mikami, a professional ghost sweeper who operates a business dedicated to exorcising spirits and supernatural entities. Mikami is a skilled and determined exorcist, often motivated by financial gain, as she charges high fees for her services. Her primary goal is to eliminate ghosts and demons, but her methods are frequently driven by a pragmatic and profit-oriented mindset. Despite her mercenary tendencies, Mikami possesses a strong sense of justice and often assists those in need, even if it means bending her own rules.

The series introduces Tadao Yokoshima, a bumbling and perverted assistant who becomes Mikami's reluctant partner. Yokoshima's incompetence and lecherous behavior often lead to comedic situations, creating a dynamic contrast with Mikami's no-nonsense personality. Despite his flaws, Yokoshima occasionally proves useful, and his presence adds a layer of humor to the narrative. Another key character is Okinu, a young ghost girl who becomes Mikami's apprentice. Okinu's innocence and eagerness to learn provide a counterbalance to Mikami's hardened demeanor, and her growth as a ghost sweeper is a recurring theme throughout the series.

The episodic structure of the series explores various supernatural cases, ranging from haunted houses and cursed objects to malevolent spirits and ancient demons. Each case presents unique challenges, often blending horror, action, and comedy. Mikami employs a variety of tools and techniques, including talismans, spiritual energy, and her signature weapon, the "GS Mikami" exorcism gun, to combat supernatural threats. The series also delves into the personal lives of the characters, revealing glimpses of their pasts and motivations, which add depth to their interactions and decisions.

As the story progresses, larger arcs emerge, involving powerful entities and conspiracies that threaten both the human and spirit worlds. These arcs often test Mikami's resolve and force her to confront her own beliefs and limitations. The series balances its episodic format with overarching plotlines, maintaining a cohesive narrative while allowing for standalone adventures. Themes of redemption, morality, and the coexistence of humans and spirits are explored, often through the lens of Mikami's evolving relationships with Yokoshima, Okinu, and other recurring characters.

"Ghost Sweeper Mikami" combines supernatural action with comedic elements, creating a distinctive tone that appeals to fans of both genres. The interplay between the main characters, coupled with the diverse array of supernatural cases, ensures a dynamic and engaging storyline. The series' blend of humor, horror, and character development makes it a memorable entry in the genre, offering a mix of lighthearted entertainment and deeper thematic exploration.